Articular cartilage thickness alterations in hind limb of young and aged PAC1 gene-deficient mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide which was shown to be released in the hypothalamo-hypophyseal system but subsequently demonstrated in the entire nervous system and nearly all peripheral organs, including skeletal elements. PACAP has an important function in the regulation of chondrogenic differentiation, protecting in vitro chondrogenesis during various stresses and in osteogenesis. PACAP knockout (KO) mice show early signs of aging. Its most potent receptor is PAC1-R, the activation of which leads to enhanced Sox9 expression and subsequently, increase in the expression of collagen type II, glycosaminoglycans, and aggrecan. In the present experiments, we investigated the effect of the absence of PAC1 receptor in PAC1 KO homozygous and heterozygous mice focusing on joints of hind limb in young and aged animals. Thickness and extracellular matrix content of articular cartilage of joints increased in the absence of PAC1 receptor with aging. A thicker cartilage was detected in aged animals in mechanically affected joints. Interestingly, the disturbance of PACAP signaling pathways increased the nuclear translocation of P-Sox9 transcription factor in various joints. In summary, the alteration of PAC1 receptor regulated signalization elevated cartilage formation and protected cartilage architecture during aging suggesting a balancing effect of the receptor in chondrogenesis.